Molecular Dynamics Simulations of the Structure of Lipid-Based Nanomaterials

Lipid based nanomaterials are being considered as promising nanocarriers for a variety of therapeutic approaches including for example drug delivery, siRNA gene silencing, mRNA vaccines (as those for COVID-19). When the active substances to be delivered are nucleic acids, which are negatively charged in water, the lipid formulation includes typically a ionizable cationic lipid which is believed to interact with the nucleic acid and help protect it from degradation. However only limited information is available about the internal arrangement of the mRNA inside the nanoparticle. Here we report the results of multiscale molecular dynamics simulations used to characterize the structure of a lipid-based nanomaterial composed of messenger RNA and lipid formulations containing ionizable cationic lipids. In particular, the role of pH in the formation of the mRNA-lipids complex has been investigated. The simulations have shown that the interaction between the ionizable cationic lipids and RNA is attractive only at low pH and effectively repulsive at high pH. In addition, the ionizable lipid, when uncharged, also shows a significantly increased flip-flop probability, which may have consequences in the process of fusion of the nanoparticle with the endosomal membrane.